14-dehydro and 15-dehydro-11-oxygenated progesterones



United States Patent 0 3,021,327 14-DEHYDRO AND IS-DEHYDROJl-OXY- GENATED PROGESTERONES Philip F. Bea] IH, Kalamazoo, and Robert W.

Kalamazoo Township, Kalamazoo County, Micln, assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed July 20, 1961, Ser. No. 125,386

21 Claims. (Cl. 260-23955) This invention relates to novel 14-dehydro and lS-dehydro-l1-oxygenated-progesterones, the IS-methyl derivatives thereof and the corresponding 3,20-bis(alkylene ketals) of all of these compounds. It is particularly concerned with 11(a and ,8)-hydroxy-4,l4-pregnadiene-3,20-

3,021,327 Patented Feb. 13, 1962 ice diones and the corresponding ll-keto analogues, IS-methy1-11(a and fi)-hydroxy-4',14-pregnadiene-3,ZO-diones and the ll-keto counterparts thereof, ll-( e and fi)-hydroxy-4, ,IS-pregnadiene-S,ZO-diones:and the corresponding ll-keto analogues, LS-methyl-llh and B)-hydroxy-4,15-pregnadiene-3,20-diones, 15-methyl-4,l5-pregnadiene-3,11,20-trione, and the corresponding 3,20-bis(alkylene ketals) of all of these compounds, and processes for preparing same. The novel compounds of this invention also include 15- methylene-l1(a and [3)g-hydroxy and ketoprogesterones, the 3,20-bis(alkylene ketals) thereof and processes therefor.

The compounds of this invention and a process of production thereof are illustratively represented by the following sequence of formulae: (3H3 CH 0:0

to X

whereinX is selected from the group consisting of chlorine and bromine; R is selected from the group consisting of hydrogen and. methyl; is a generic expression denoting.

a. and B-bonds and mixtures thereof; the symbol wherein n is selected from the integers one and two and R is selected from the group consisting of hydrogen and a lower-alkyl' radical containing from one to six carbon atoms, inclusive.

The novel compounds of this invention possess valuable pharmacological properties such as tranquilizing, central nervous system depressing, analgetic, sedative, salt regulating and anti-inflammatory activities and consequently are useful in the treatment of nervous disorders, hypertension, congestive heart failure, allergic reactions, rheumatoid arthritis and related illnesses in both humans and valuable domestic animals. These compounds can be prepared and administered to mammals, birds, humans and animals in a wide variety of oral and parenteral dosage forms, singly, or inadmixture with other coacting compounds. They can be associated with a carrier which can be a solid materia or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, pills or the like, preferably in unit dosage forms for simple administration or precise dosage. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups or elixirs. The novel compounds of this invention which particularly possess the aforementioned valuable pharmacological and therapeutic usefulness have the formulae: v 1

and

wherein X is selected from the group consisting of the fi-hydroxymethylene radical the a-hydroxymethylene radical radicals are of the formula 0-(0Hz)s wherein n is selected from the integers one and two and R is selected from the group consisting of hydrogen and a lower-alkyl radical containing from one to six carbon atoms, inclusive.

Besides the above-noted therapeutic uses of the novel progesterones of this invention, these compounds are additionally valuable in that they can be employed in the production of new and useful further substituted progesterones, cortisones and hydrocortisones and their corresponding 9a-fluoro and l-dehydro analogues. For example, 14-dehydro-ISB-methylprogesterone can. be con.- verted to l5fi-methylhydrocortisone and lSfi-methylcortisone and their corresponding l-dehydro and 9q-halo analogues; the lS-dehydro counterparts can be utilized in the preparation of l5a-rnethylhydrocortisone. and l5a-methylcortisone and their corresponding l-dehydro and 9a-ha1o analogues.

The novel compounds of the present invention are prepared from 15a-hydroxy-4-pregnene-3,11,20-trione (I) by the following reactions: The triketo compound (I) is converted to a corresponding 3,20-bisketal (III) by the method disclosed in U.S. Patent 2,773,060 using the ketal forming agents disclosed therein, i.e., an alkane-1,2-diol or alkane-l,3-diol such as, ethylene glycol, propane-1,2 diol, propane-1,3-diol, butane-l,2-diol,' pentane-l,2-diol, 3-methylpentane-l,2-diol, hexane-1,3-diol, octane-1,2-diol and the like. The ketal groups at the 3 and 20-positions are thus each of the following general formula:

wherein R is a member of the group consisting of hydrogen and a lower-alkyl group and n is an integer from one to two, inclusive. Ethylene glycol is the preferred diketalizing agent.

The next step of the process of this invention for the preparation of the 14-dehydro compounds of Formulae VI and X, wherein R is hydrogen, involves dehydrating a l5a-hydroxy 4 pregnene-3,11,20-trione 3,20-bis(alkylene ketal) (III) e.g., by preparing a mixture of the 15e-tosylate and lifi-ChlOro derivatives with p-toluenesulfonyl chloride and pyridine and treating with collidine to produce a 4,l4-pregnadiene-3,l1,20-trione 3',20-bis(alkylene ketal) (IV'). Reducing the thus obtained 14-dehydro compound (IV) e.g.', with lithium-aluminum hypregnadiene-3,20-diones (VI).

dride in an organic solvent inert to the reaction such as tetrahydrofuran, yields an 11fi-hydroxy-4,l2-pregnadiene-3,20-dione 3,20-bis(alkylene ketal) (V) while re duction with sodium in alcohol yields an lla-hy'droxy- 4,14-pregnadiene-3,20-dione 3,20-bis(alkylene ketal) (V). Hydrolysis of the 3,20-diketal substituents of the thus obtained ll-hydroxy compounds (V) can be carried out employing conventional hydrolytic methods, e.g.,, under very mild conditions such as using dilute aqueous acid at room temperature, to give 11(a and ;8)-hydroxy-4,14- The lla-hydroxy compounds of Formula VI can be converted to the corresponding llfi-hydroxy counterparts by oxidation, e.g., with chromium trioxide in acetic acid or acetone, to pro- .duce the corresponding ll-keto compound (X), which is then diketalized to yield a 4,14-pregnadiene-3,11,20-trione 3,20-bis(alkylene ketal) (IV); reaction of the thus obtained product'(IV) with lithium aluminum hydride in an inert solvent followed by ketal hydrolysis yields l1fl-hydroxy-4,l4-pregnadiene-3,20-dione (VI). The 11- keto compounds represented by Formula IV can be hydrolyzed in the same manner as the ll-hydroxy compounds of Formula V to yield the corresponding 4,14- pregnadiene-3,1 l,ZO-trione (X). The compounds of Formula X can also be obtained by an alternative route comprising: reacting lfia-hydroxy- 4-pregnene-3,11,20-trione (I) with a suitable halogenating agent to give the corresponding 15-halo-4-pregnene- 3,11,20-trione (II) (the 15-halo derivative produced is chloro when p-toluenesulfonyl chloride and pyridine is employed; use of N-bromoacetamide gives the corresponding 15-bromo derivative); dehydrohalogenating either of the thus obtained 15-halo compounds (II), e.g., by heating at refluxing temperatures with a tertiary aromatic amine such as pyridine, collidine and lutidine, yields 4,l4-pregnadiene-3,11,20-trione (X).

In the preparation of the 14-dehydro compounds of Formulae VI and X wherein R is methyl, the starting material employed is a lcx-methyl-15B-hydroXy-3J1,20-

. ISa-rhethyl 1518 hydroXy-3,11,20-trione 3,20 bis(alkydene ketal) (VIII). Dehydration of the compound of Formula VIII, e.g., with thionyl chloride, produces a l5-methyl 4,14 pregnadiene-3,11,20-trione 3,20-bis (alkylene ketal) (IX). Reducing the thus obtained 15- methyl compound (IX) in the same manner as disclosed above for the corresponding IS-hydrogen counterpart (IV) yields a 15-rnethyl-1l(a and B)-hydroxy-4,14-pregr 12 V In preparing the IS-dehydro compounds of Formulae XIV and'XV, wherein R is hydrogen, the starting material employed is a 15/3-hydroxy- 1l-ketoprogesterone 3,20-bis(alkylene ketal) '(Xl). Theproduction of such a compound (XI) can be carried out by reducing the l5- keto group of a compound of Formula VII (prepared as described above), e.g., with a metal borohydride such as sodium borohydride suspended in a suitable solvent. The reaction of the ISB-hydroxy-ll-ketoprogesterone 3,20-dione 3,20-bis(alkylene ketal) (XI) with dimethyl carbonate and an alkali-metal hydride yields a 15,8-hydroxy 4 pregnene-3,11, 20-trione 3,20-bis(alkylene ketal), l5-methyl carbonate (XII). Loss of CO0 and CH OH from the compound of Formula XII occurs at the 15-position on heating, preferably under vacuum, to yield a 4,l5-pregnadiene-3,11,20-trione 3,20-bis(a1kylene ketal) (XIII). The thus produced compound (XIII) is reduced to an 11(oz and ,8)-hydroxy-4,IS-pregnadiene- 3,20-dione 3,20-bis(alkylene ketal) (XIIIa) in the same manner as disclosed for reducing an 11-keto-4,14-pregnadiene (IV) to yield a compound of FormulaV, above. Hydrolysis of the 15-dehydro-3,20-diketals of the 11- hydroxy compounds (XIIIa) to produce their corresponding 3,20-diketones (XIV), can be carried out in the manner shown above for the conversion of the 14-dehydro-3,20-diketals (V) to their corresponding 3,20-diketones (VI). The lla-hydroxy compoundsof Formula XIV can be converted to their corresponding llfi-hydroxy counterparts in the same manner as for the 14- dehydro compounds of Formula VI disclosed above. In the same manner as disclosed above for the hydrolysis of the 3,20-diketals of the 14-dehydro compound (IV) to form the corresponding 3,11,20-triketone (X), the 15- dehydro 3,20- diketals of Formula XIII are converted to eir corresponding 3,11,20-triones (XV).

The 15-dehydro compounds of Formulae XIV and XV, wherein R is methyl, are prepared from a 15ccmethyl 15 hydroxy 4 pregnene 3,11,20 trione 3,20-bis(alkylene ketal), IS-methyl carbonate ester (XVI). A 15u-methyl-15,8-hydroxy-4-pregnene-3,1 1,20- trione, 3,20-bis(alkylene ketal) (VIII) (prepared as disclosed above) is reacted with dimethyl carbonate and an alkali-metal hydride to produce a compound of Formula XVI. Pyrolysis of the carbonate, ester. of the thus produced compound (XVI) yields a 15-methyl-4,15-

pregnadiene 3,11,20-trione 3,20 bis(alkylene ketal) nadiene3,20-dione 3,20-bis(alky1ene ketal) (IXa). Hy-

drolysis of a IS-methyl compound of Formula IXa in the same manner as described above for the corresponding IS-hydrogen counterpart (V), yields a IS-methyl com- (XVII). A compound of Formula XVII is reduced to an 11(nc and 5)-hydroxy-4,15-pregnadiene-3,ZO-dione 3,20-bis(alkylene ketal) (XIIIa) in the same manner as disclosed above for the reduction of an l1-keto-4,l4- pregnadiene (IV) to yield the corresponding 11-hydroxy compound (V). Hydrolysis of the IS-methyl-lS-dehydro 3,20-diketalsof the ll-hydroxy compounds (XIIIa) to produce their corresponding 3,20-diketones (XIV), can be carried out in the manner shown above for the conversion of the 15-hydr0gen-14-dehydro 3,20-bisketals (V) to their corresponding 3,20-diketones (VI). The 15- methyl-lla-hydroxy compounds of Formula XIV can be converted to their corresponding llfi-epimers in the same manner as shown above for the 15-hydrogen-l4-dehydro compounds (VI). Following the procedure disclosed above for the hydrolysis of the 3,20-diketals of the 15- hydrogen-14-dehydro compounds (IV) to form the corresponding 3,11,20-triones (X), but substituting a 15- methyl-4,l5-pregnadiene-3,11,20-trione, 3,20-bis alkylene ketal) (XVII) as starting material, yields the correspond ing l5-methyl-4,15-pregnadiene-3,l1,20-trione (XV).

In the preparation of the IS-methylene compounds of Formulae VII, VII'A, VII'B and VII'C, the starting material is a 4-pregnene-3,11,15,20 -tetraone, 3,2 0-bis(alkylene ketal) (VII), obtained as disclosed above in one of the steps of the process for synthesizing, the 14-dehydro-l-methyl compounds of this invention. The transformation of the l5-lreto compound (VII) to the corresponding 'lS-methyIene-LI1,20-trione-3,20-bis(alkylene ketal) (VII) is carried out along the general lines of the method of Wittig (see Ben/87, 1318 [1954], and 88, 1654 [1955]), for conversion of a carbonyl compounds into an olefin in which the oxygen atom is replaced by an alkylidene group by the action of an alkylidene triphenylphosphorane. Thus, the reaction of a 4-pregnene-3,11,15,20-tetraone 3,20-bis(alkylene ketal) (VII) with an alkyl triphenylphosphonium halide and alkyl lithium (or with a trialkylphosphonate and sodium hydride) yields a l5-methylene-3,11,20-trione-3,20- bis(alkylene ketal) ((11).

Reduction of the thus obtained l5-methylene compound (Vll') e.g., with lithium aluminum hydride in an organic solvent such as tetrahydrofuran and with, sodium in a solvent such as ethanol yields a 15-methylene- 11( 3 and a)-hydroxy-4-pregnene-3,20-dione 3,20-bis(a1- kylene ketal) respectively (VII'B). Hydrolysis of the 3,20-diketa1- substituents of the thus obtained ll-hydroxy compounds (VII'B) can be carried out employing conventional methods, e.g., using dilute aqueous acid under mild conditions such as room temperature, to give 15-methylene-11(a and B)-hydroxy-4-pregnene-3,20-dione (VII'C). The lla-hydroxy compounds of Formula VII'C can be converted to the corresponding 11,8- hydroxy counterparts by oxidation, e.g., with chromium trioxide in acetic acid or acetone, to produce the corresponding ll-keto compound (VII'A) which is then diketalized to yield a 15-methylene-4-pregnene-3,11,20- trione 3,20-bis(alkylene ketal) (VII'); reaction of the thus obtained product (VII) with lithium aluminum hydride in an inert solvent yields 15-methylene-11B-hydroxy-4-pregnene-3,20-dione (VII'C). The compounds represented by Formula VII can be hydrolyzed in the same manner as the ll-hydroxy compounds of Formula VIIB to yield the corresponding IS-methylele-4-pregnene-3,l1,20-trione (VII'A).

The 14 and 15-dehydro and IS-methylene compounds of this invention produced by the above-described methll-keto ods can be isolated from their reaction mixtures by conventional methods, for example, by pouring the reaction mixture into water and separating the resultant precipitate by filtration. Additionalpurification of the product can be accomplished by conventional methods, for example, by'recrystallization from a suitable solvent or mixture of solvents, e.g., by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as, methylene chloride-Skellysolve B (hexanes), acetone-Skellysolve B, and the like.

PREPARATION 1 15a hydroxy 11 ketoprogesterone (15a hydroxy 4- pregnene-3,11,20-tri0ne) (l) A medium was prepared of ten grams of Cerelose (dextrose) 20 grams of corn steep liquor and 1000 milliliters of water and adjusted to a pH between 5.5 and 6.

14 volume of acetone approximately equal to the volume of the mycelium, and extracted twice, each time with a volume of methylene chloride approximately equal to the volume of the mycelium. The acetone and methylene chloride extracts, including solvent, were added to the beer filtrate and the combined extracts and beer filtrates were extracted successively with two one-half by volume portions of methylene chloride and then with two one fourth by volume portions of methylene chlo- PREPARATION 2 15a hydroxy 4 pregnene 3,11,20 trione 3,20-

bis(ethylene ketal) (1 Sct-hydrOxy-I l-keloprogesteron'e 3,20-bis[ethylene kelal1) (III) A mixture of 4.75 grams of 15a-hydroxy-11-ketoprogesterone (1) (Preparation 1), 100 milliliters of benzene, 5 milliliters of ethylene glycol and 0.1 gram of paratoluenesulfonic acid was refluxed with stirring under a water trap for six hours. The mixture was then cooled and the product crystallized. The acid was neutralized by the addition of 10 milliliters of saturated sodium bicarbonate solution and the mixture stirred for fifteen minutes. The crystalline precipitate was removed by filtration and ovendried. The product Was recrystallized from acetone containing a drop of pyridine, to yield 2 grams of crystals melting at 248 to 250. A second crop furnished 0.80 gram. The original filtrate was evaporated, the residue I and also the second crop were recrystallized to yield an additional 1.12 grams of 15a-hydroxy-4-pregnene-3,1l,20- trione 3,20-bis(ethylene ketal) (III), melting at 246-248 degrees centigrade. V

Analysis.-Calcd. for C H O C, 69.42; H, 8.59. Found: C, 69.41; H, 8.42. [0L]n+62 (acetone);

7:31? 3530, 1697, 1100 01117 PREPARATION 3 I 4-pregnene-3,11,15,20-tetra0ne 3,20-bis-(ethylene ketal) Twelve liters of this sterilized medium was inoculated grams of ll-ketoprogesterone, dissolved in 100 milliliters of acetone. After an additional 24 hour period of incubation under the same conditions of temperature and aeration, the beer and mycelium were separated. The

(11,15 diketoprogesterone 3,20-bis[ethylene ketal]) (VII '1l,15,20-tetraone 3,20-bis(ethylene ketal) (VII) with melting point 208-210" and rotation [ab 16 degrees (acetone).

PREPARATION 4 15 fl-hydroxy-I I -ketopr0gester0ne 3,20-bis(erhylene kezal) (15,8-hydroxy-4-pregnene-3J1,20-iri0ne 3,20-bis[ethylene ketalJ) (XI) A solution of 11,15-diketoprogesterone, 3,20-bis(ethylene ketal) (VII) (Preparation 3) (12.4 g.) in 200 milliliters of purified tetrahydrofuran was added to one liter of mycelium was filtered, washed. twice, each time with a isopropyl alcohol. Thereupon 2.1 grams of sodium borofiltration.

15 hydride and 20 milliliters of water was added and the mixture stirred at room temperature for 3% hours. The excess borohydride was destroyed by the addition of a few drops of acetic acid. The mixture was thereupon neutralized by the addition of saturated sodium bicarbonate. The reaction mixture was allowed to evaporate under the hood. The residual material was partitionedbetween methylene chloride and water, and the organic layer was separated, filtered, and evaporatedunder reduced pres sure to give a residue. This residue was dissolved in hot methanol, filtered, and allowed to-crystallize to give 8.8 grams of lfi-hydroxy-1l-ketoprogesterone 3,20-bis(ethylene ketal) (XI). A sample which was crystallized twice more from methanol melted at 205 to 208 degrees centigr'ade. I

PREPARATION 5 a methyl-15fl-hydroxy-4-pregnene-3J1,ZO-Iriane 3,20- bz's( ethylene ketal) (15a-methyl-155-hydr0xy-11-ket0- progesterone 3,20-bis[elhylene ketall) (VIII) A solution was prepared containing 1.15 grams of 4- pregnene- 3,11,l5,20 -tetraone 3,20-bis(ethylene ketal) (VII) (Preparation 3) in 50 milliliters oftetrahydrofuran. This solution was cooled in an ice bath and thereto was added milliliters of acornmercial three-molar methyl magnesium bromide solution in ether. The ice bath was removed and the reaction stirred at room temperature for five hours. The reaction mixture was then decomposed by the addition of a saturated ammonium chloride solution. The liquid was decanted from the solids and filtered. The solids were washed with methylene chloride. The methylene chloride washings were added to the filtrate and the filtrate was allowed to evaporate yielding 1.07 grams of material which was recrystallized from acetone Skellysolve B hexanes to give l5a-methyl-l5fl-hydroxy-4- pregnene-3,1l,20-trione 3,20-bis(ethylene ketal) (VIII) of melting point 206 to 210 degrees centigrade- Analysis.-Calcd. for C H O C, 69.93; H, 8.58. Found: C, 69.97; H, 8.86. [a1 (acetone)+15;

villi? 354.0, 3400, 1695, 1 670, 1163, 1095, 1025 cm.-

7 EXAMPLE 1 V 4,14-pregnadiene-3J1,204ri0ne 3,20-bis(ethylene ketal) (14 dehydro -.l1 keto-progesterone 3,20-bis[ethylene ketalJ) (IV) A mixture of 4.6 g. of 15a-hydroxy-4-pregnene-3J1,20- trione 3,20-bis(ethylene ketal) (III) (Preparation 2), 4 g. of p-toluenesulfonyl chloride and ml. of pyridine was heated on a steam bath, with stirring, for a period ofabout five hours. The pyridine was removed under vacuum and 20 ml. of collidine then'added to the reaction mixture, which was heated at refluxing'temperature for a period of about 20 minutes. The mixture was cooled and 200 ml.

1&3 3,20-bis(ethylene ketal) (IV) in 20 ml. of acetone was diluted with 2.5 ml. of-water containing 3 drops of concentrated sulfuric acid. After standing for about 15 hours at room. temperature (about 22m 25 C.) the acidity of'the reaction mixture was neutralizedv with saturated sodium bicarbonate and thesolvent removed under vacuum The residue was partitioned with methylene chloride and water and filtered to remove the undissolved solids. The filtrate was separated and the methylene chloride layer allowed to evaporate.v The solids therefrom were recrystallized from methanol to yield the product, light-colored crystals'of 4,l4-pregnadiene-3,l1,20- trione (X).

, EXAMPLE 2 11p hydroxy 4,14 pregnaa'iene 3,20 4 dione 3,20 bis (ethylene ketal (14-dehydr0-I IB-hydroxy-progesterone ,320-bislethylene kezal] (V) To a solution of 10 g. of lithium aluminum hydride suspended in 800 m1. of ether was added 10 g. of 4,14- pregnadiene-3,11,20-trione 3,20-bis(ethylene ketal) (IV) dissolved in 500 ml. of ether. This mixture was stirred for a period of about minutes at room temperature after which time it was'heated at refluxing temperature for about one hour, then cooled. and hydrolyzed with water. The precipitate that resulted was extracted repeatedly with ether and the combined ether extracts evaporated after washing with water. and drying wit anhydrous sodium sulfate. The resulting crystalline residue was 11B-hydroxy-4,14-pregnadiene-3,20-dione -3,20-bis(ethylene ketal) (V).

EXAMPLE 2A 114: hydr0xy-4,14 pregnadiene 3,20 dione 3,20 bis- (ethylene ketal) (V) To a solution of 05g.- of 4,l4-pregnadiene-3,l1,20-

' trione 3,20-bis(ethylene ketal) (1v in ml. of norof ether added thereto; the solid material was removed by Thev solvents were removed from the filtrate by vacuum distillation and the resulting residue dissolved in methylene chloride and chromatographed over a column of 350 g. of Florisil (synthetic magnesium silicate). The

.product which weighed 2.06 g. was eluted with a mixture of 5% acetone in Skellysolve B (hexane hydrocarbons). .The product was recrystallized from methanol to yield 1.15 g. An additional crystallization from methanol yielded an analytical sample of pure, crystalline 4,14-pregnadiene-3,'l1,20-trione 3,20-bis(ethylene ketal) (IV) with a :31? 1706, 1665, 1157, 1090, ioztcmr EXdMPLE--1A- v 0, 72.43; tr, V8.27.

' 4,14-pregmzdiene-3J1,ZO-triane (I4-dehydro-1l-ketoprogesterone) (X) 7 'A' solution or 1 g. of 4,14-pregnadiene-3fl1,20-trione ing mal propylalcohol at reflux temperature, is added 5 g. of sodium in small pieces. After a' period of about one hour, methanol is added to decompose the remaining nnreacted sodium. To the reaction mixture is thereupon added 50 ml. of water and the mixture distilled until the product separates from it. The crude product is removedfrom the essentially aqueous medium by' filtration and is recrystallized from a mixture of chloroform and ethanol to give pure, light-colored crystalline 11oz hydroxy 4,14 pregnadiene his (ethylene ketal) (V).

3,2 0 f dione I 3,20-

EXAMPLE 3 Y I1,8-hydf0xy-4,14-pregnadiene-3,20-dione (1 4-dehydro 1 Ifl-hydroiyprogesterone) (VI) I drops of concentrated sulfuric acid and allowed to stand at room temperature (about 22 to 25 C.) for a period of approximately 15 hours. The mixture was neutralized with saturated sodium carbonate and the acetone removed' under vacuum. The product was extracted with methylene chloride, chromatographed over a column of Florisil and eluted therefrom with solvent fractions containing acetone in Skellysolve B. Recrystallization from acetone yielded light-colored crystals of pure lip-hydroxy-4,14-pregnadiene-3,20-dione (VI).

EXAMPLE 3A 11 u-hydroxy-4J4-pregnadiene 3,20-di0ne l4-dehydro- 11 whydroxyprogesterone) (VI Following the procedure of Example 3, but employ- 1 1u-hydroXy-4,14 pregnadiene-3,20-dione 3,20-bis- (ethylene ketal) (V) as starting material, yields llahydroxy-4,l4-pregnadiene-3,20-dione (VI), a lightcolored crystalline solid.

EXAMPLE 3B 1a-lzydr0xy-4,14-pregnaa'iene-3,20-dione (VI) A solution of 0.2 g. of chromium trioxide in 10 ml. of acetic acid, 1.5 ml. of Water and 0.02 ml. of concentrated sulfuric acid was added dropwise to a solution of 0.3 g. of 1lp-hydroxyl,14-pregnadiene-3,20-dione (V1) in 10 ml. of acetic acid and 1 ml. of water at a temperature of about C. The resulting solution was poured into a mixture of about 100 ml. of ice and water. The mixture was extracted with methylene chloride, the extract washed with water until the washings were neutral and then dried over anhydrous sodium sulfate. Concentration of the dried methylene chloride solution gave an oily residue which was crystallized from ether to yield light-colored crystalline 4,14-pregnadiene-3,11,20- trione (X). A solution containing 0.2 g. of this product, 5 ml. of ethylene glycol and 0.2 g. of p-toluene-sulfonic acid in 100 ml. of benzene was refluxed for a period of about 18 hours. The water initially present and formed during the reaction was continuously removed with a Dean-Stark separator. The cooled solution was washed with dilute aqueous sodium carbonate, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue was crystallized from hexane to yield light-colored crystals of 4,l4-pregnadiene-3,11,20- trione 3,20-bis(ethylene ketal) (IV). To a solution of 0.1 g. of this product in ml. of n-propanol, 1 g. of sodium was added. After the sodium was dissolved, the reaction mixture was diluted with water and extracted with methylene chloride. The methylene chloride was evaporated under vacuum; the oily residue remaining was dissolved in 5 ml. of methanol, 3 ml. of acetone and 1 ml. of 5 N hydrochloric acid and heated at refluxing temperature for a period of about 1 hour. The solution was cooled, diluted with water and extracted with methylene chloride; the extracts were washed with water until the washings were neutral. The methylene chloride extracts were concentrated to a semicrystalline residue which was dissolved in a mixture of ether and hexane, from which light-colored crystals of 1la-hydroXy-4,14-pregnadiene-3,20-dione (VI) was obtained.

EXAMPLE 4 J5 methyl 4,14 pregnadiene 3,11,20 trione 3,20- (bis(ethylene ketal) (14-dehydr0-15-methyl-1I-ketoprogesterone 3,20-bislezhylene kez'all) (IX) A solution of 1 g. of lSu-methyl-lSfl-hydroxy-ll-ketoprogesterone 3,20-bis(ethylene ketal) (Vill) in 10 ml. of pyridine was cooled to a temperature of about 0 C. 0.8 ml. of thionyl chloride was added dropwise to the solution with stirring; following about ten minutes of stirring, the mixture was poured over ice and the crystalline product (0.85 g.) separated therefrom by filtration. Recrystallization of this material yielded 0.75 g. of l5-methyl-4,l4-pregnadiene-3,11,20-trione 3,20-bis- (ethylene ketfl) (IX) with a melting point of 133 to 134 C.

Analysis.Calcd. for C H G C, 72.86; H, 8.48. Found: C, 73.17; H, 8.68.

:52 1701, 1.675, 1658, 1150, 1035 cm? EXAMPLE 5 I 5-methyl-4,14-pregnadiene-3,J 1,20-tri0ne (14-dehydr0- J 5 -metilyZ-1 J -kezopr0gesterorie) (X) A solution of 11.39 g. of 15-methyl-4,l4-pregnadiene- 3,11,20-trione 3,20-bis(ethylene ketal) (IX) in 250 ml. of acetone was diluted with 25 ml. of water containing 25 drops of concentrated sulfuric acid. After standing at about 22 to 25 C. for a period of about 15 hours, the mixture was neutralized with saturated sodium bicarbonate solution and the acetone removed under vacuum. The product was extracted with methylene chloride, chromatographed over 1 kg. of Florisil and eluted 18 with portions of 10 and 15% of acetone in Skellysolve B. 5.94 g. of product was recovered on elution with the 15% acetone-Skellysolae B fractions. A sample of this material was crystallized and melted at 128 to 134 C.; its infrared spectrum was identical to that of 15- methyl-4,14-pregnadiene-3,11,20-trione (X) prepared by the N-bromoacetamide-suliur dioxide-pyridine dehydration of 1Six-methyl-15/i-l1ydroXy-4-pregnene-3,l1,20-trione.

EXAMPLE 6 15-methyl-11,8-hydr0xy-4,14-pregnadiene-3,20-dione 3,20-

bis(ezhylene ketal) (15 -methyl-14-dehydr0-1I S-hydronprogesterone 3,20-bis (ethylene ketal) and 15- methyl 11oz hydroxy 4,14-pregnadiene-3,20-dione 3,20 bis(ethylene ketal) (15-methyl-14-dehydr0-I1cchydroxyprogesterone 3,20-bis(ethylene ketal) (IXa) Following the procedure of Example 2, but employing 15-methyl-4,14-pregnadiene-3,11,20-trione 3,20-bis(ethylene ketal) (IX) as starting material, yields 15-methyl- 11,3 hydroxy 4,14 pregnadiene-3,20-dione-3,20 bis- (ethylene ketal) (IXa) EXAMPLE 7 15 methyl 11fl-hydroxy- IJ4-pregnadiene-3,20-dione (14-dehydr0-15-methyl-J 1fi-hydroxyprogesterone) (VI) Following the procedure of Example 3, but substituting 15-methyl-11,6-hydroXy-4,14-pregnadiene-3,20-dione 3,20- bis(ethylene ketal) (IXa) as starting material, yields 15- methyl-1 1fl-hydroXy-4,14-pregnadiene-3,20-dione (XI) EXAMPLE 7A 15-methyl-11a-hydroxy-4,14-pregnadiene-3,20-dione (14- dehydra-I 5 -methyl-] 1 a-hydroxy-progesterone) (VI) Following the procedure of Example 3, but employing IS-methyl-l1a-hydroxy-4,14-pregnadiene-3 ,ZO-dione 3,20- bis(ethylene ketal) (IXa) as starting material, yields 15- methyl-1 1a-hydroxy-4,14-pregnadiene-3,20-dione (VI) EXAMPLE 7 B 15-methyl-1 1 a-hydroxy-4,14-pregnadiene-3,ZO-dione (VI) Following the procedure of Example 3B, but substituting 15-methyl-l1,6-hydroxy-4,14-pregnadiene-3,20-dione (VI) as starting material, is productive of 15-methyl-11u-hydroxy-4,14-pregnadiene-3,20-dione (VI).

EXAMPLE 8 15,3-hydroxy-4-pregnene-3,11,20-tri0ne 3,20-bis( ethylene ketal), 15 -methyl carbonate (JSH-Izydroxy-Il-ketaprogesterone 3,20-bisiethylene ketal], 15-methyl carbonate) (XII) A mixture of 7 g. of 15fi-hydroXy-1l-ketoprogesterone 3,20-bis(ethylene ketal) (Xi) (Preparation 4), ml. of dimethyl carbonate and 240 m1. of benzene was distilled under nitrogen until 25 ml. of distillate was removed. 8 g. of a 52% mineral oil suspension of sodium hydride was added to the mixture, which was then heated at refluxing temperature for a period of about 15 hours. The mixture was then cooled, filtered through Celite (diatomaceous earth) and the filtrate distilled under vacuum to remove the solvent. The residue was dissolved in hot methanol and filtered;'4.08 g. of product crystallized from-the filtrate on cooling. A sample of this material was recrystallized from methanol and yielded pure 1513- hydroxy 4 pregnene-3,11,20-trione 3,20-bis(ethylene ketal) 15-methyl carbonate (XII) melting at 199 to 201 C.

Analysis.Calcd. for C H Q C, 66.10; H, 7.81. Found: C, 66.35; H, 7.94.

will? 1738, 1706, .1688 cm."

The structure expected for this compound was confirmed by its nuclear magnetic resonance spectrum.

bis (ethylene ketal) (XHIa) EXAMPLE 9 4,15-pregnadiene-3,1I,ZO-trione 3,20-bis(ethylene ketal) (15 dehydro II-ketoprogesterone 3,20-bis[ethylene keral1) (X111) 2 g. of 15fi-hydroxy-4-pregnene-3,11,20-trione 3,20- bis(ethylene ketal), 15-methyl carbonate (XII) was heated under vacuum in a Woods metal bath with magnetic stirring. The flask was placed in the bath at an initial temperature of 300 C. and over a period of about 10 minutes the heat was increased until it reached 350 C.; by this time the bubbling in the reaction flask had nearly ceased and a crystalline sublimate was present; on cool- .ing, the contents of the flask crystallized. The infrared spectrum of this total crude material indicated that the absorption band due to the carbonate ester was lost. The crude residue was dissolved in boiling methanol containing one drop of pyridine and filtered. The product, weighing 1.03 g., crystallized from the solvent on cooling and melted at 195 to 200 C. Two further crystallizations from methanol yielded an analytical sample of 4, 15-pregnadiene-3,l1,20-trione 3,20-bis(ethylene ketal) (XIII), melting at 205 to 207 C. V

Analysis-Calm. for C H O C, 72.43; H, 8.27. Found: C, 72.19; H, 8.42.

The nuclear magnetic resonance spectrum of this compound confirmed the A bond by a doublet of doublets centering at 351 c.p.s. downfield from tetramethylsilane at 60 megacycles.

EXAMPLE 4,15 pregnadz'ene-3,1I,20-trione (IS-dehydro-II-ketoprogesterone) (XV) To suspension of 20.7 g. of 4,15-pregnadiene-3,11,20- trione 3,20-bis(ethylene ketal) (M11) in 500 ml. of acetone, 100 ml. of water containing 5 ml. of concentrated sulfuric acid was added. After stirring the mixture for a period of about 16 hours at room temperature (22 to 25 C.) the steroid dissolved. The mixture was then neutralized with saturated sodium bicarbonate solution and the solvent reduced under vacuum to a volume of 150 ml. The residue was partitioned between methylene chloride and water. The organic layer was separated and washed well with water and the solvent removed, leaving a residue. The residue was treated with acetone to give 7.2 g. of crystals melting at 198 to 204 C. Concentration of the mother-liquor yielded 2.2 g. of a second crop melting at 192 to 201? C. This material was dissolved in m1. of methylene chloride and 50 m1. of acetone, and the solution evaporated on a rotary evaporator without heating until crystallization occurred. The thus obtained 4, 15-pregnadiene-3,11,20-trione (XV), had a melting point of 204 to 208 C. V

Analysis.-Calcd. for C 'H O C, 77.27; H, 803. Found: C, 77.14; H, 8 .60.

E2? 1710 cm. (sat; C=O), 1670 cm." (oonj. C=O) 1615 cm.- (A C=C) EXAMPLE 11 11fl-hydroxy-4J5-pregnadiene-3;20-dione 3,20-bis(ethyl- 1 me ketal) (15-dehydr0-JIB-hydroxyprogesterone 3,20- bis[ethylene ketall) and 11u-hydr0xy-4J5-pregnadiene-3,20-di0ne 3,20-bis(ethylene ketal) (IS-dehydro- J] oehydroxyproges terone 3 ,20bis[ethylene ketal]) (XIIIa) V Following the procedure of Example 2, but substituting 7 4,15 pregnadiene-3,11,20-trione-3,20-bis(ethylene ketal) (XIII) as starting material, yields 11B-hydroxy-4,15- pregnadiene-3-,20-dione 3,20-bis(ethylene ketal) (XIIIa) and 11a-hydroxy-4,l5-pregnadiene-3,11,20 trione 3,20-

Found: C, 72.66; H, 8.44.

20 EXAMPLE 12 11/3 hydroxy-4,15-pregnadiene-3,20-dione (IS-dehydro- Ilfl-hydroxyprogesterone) (XIV) Following the procedure of Example 3, but substituting 1 1p-hydroxy-4,15-pregnadiene-3,20-dione 3,20-bis(ethylene ketal) (XIIIa) as starting material, yields llp-hydroxy-4,15-pregnadiene (XIV).

EXAMPLE 12A 1 I a-hydr0xy-4J 5 -pregnadiene-3,20-dione (I S-dehydro- I I a-hydroxyprogesterone) (XIV) Following the procedure of Example 3, but employing 1 1a-hydroxy-4, 15 -pre gnacliene-3,20-dione, 3,20-bis ethylene ketal) (XIIIa) as starting material, yields Ila-hydroxy-4, 15 -pre gnadiene-3,20-dione (XIV) EXAMPLE 13 15 methyl 155 hydroxy 4 pregnene 3,11,20-

trz'one 3,20-bis(ethylene ketal), IS-methyl carbonate ester (15,8-hydroxy-1 1 -ket0pr0gester0ne 3,20-bis[ethylene ketal], 15-methylcarbonate ester) (XVI) A mixture of 12 g. (28.4 millimoles) of lit-methyl- 15;3-hydroxy-4-pregnene-3,1 1,20-trione 3,20-bis (ethylene ketal) (VIII) (Preparation 5), 240 ml. of dimethyl carbonate and 430 ml. of benzene was placed in a flask equipped with a Dean-Stark water trap. The mixture was stirred and heated at refluxing temperature on a steam bath for about 15 minutes. The flask was provided with a nitrogen atmosphere, 14 g. of a 52% dispersion of sodium hydride in mineral oil was added cautiously and the reaction mixture stirred while heating at refluxing temperatures for a period of about 24 hours. The reaction mixture was filtered through a Celite pad; the residual sodium hydride was carefully decomposed with tertiary butyl alcohol. The filtrate was concentrated by vacuum distillation with heat generated by a hot water bath kept at 60 C. to yield a gummy crystalline mass. The total crude product was dissolved in 500 ml. of methylene chlo ride and chromatographed over 800 g. of Florisil. The first four 500 ml. fractions of 10% acetone in Skellysolve B removed mineral oil and traces of less polar impurities; the product was eluted in fractions 6 to 9, inclusive, with 15% acetone in Skellysolve B and on recrystallization from methanol yielded 11.2 g. (22.2 millimoles or 78.3% of theoretical) of pure 15a-methyl-15 8-hydroxy-4-pregnene-3,11,20-trione 3,20-bis(ethylene ketal),15-methylcarbonate ester (XVI) with a melting point of 164 to 166 C. and a rotation [(11 of +12 (chloroform).

Analysis.-Calcd. for C H O C, 66.70; H, 8.0. Found: C, 66.79; H, 8.07.

EXAMPLE 14 I5-methyl-4,15-pregnaa'iene-3,I1,20-trione 3,20-bis( ethylene ketal) (IS-dehydro-IS-methyl-lI-ketoprogesterone 3,20-bis [ethylene ketal]) (XVII) A 200 ml. flask containing 10 g. of 15a-methyl-15B- hydroxy 4 pregnene 3,11,20 trione 3,20 bis(ethylene ketal), IS-methylcarbonate ester (XVI) was evacuated and then placed in a Woods metal bath having a temperature of about 230 C. The steroidal material was heated with stirring for about 5 minutes while the bath temperature rose to 260 C. and the molten mass bubbled vigorously as the carbonate ester was pyrolyzed. The flask was removed from the bath, cooled and the glassy contents dissolved in ml. of methanol; crystallization occurred almost immediately following solution. After cooling, the mixture was filtered and gave 7.48 g. of crystalline 15-methyl-4,15-pregnadiene-3,1 l,20-trione-3,20-bis- (ethylene ketal) (XVII) with a melting point of 127 to 133 C. and a rotation [0:1 of +42 (chloroform).

Analysis.-Calcd; for C H O C. 72.86; H, 8.47.

EXAMPLE 15 15 methyl 11p hydroxy 4,15 pregnadiene 3,20- dione 3,20-bis(ethylene kctal) (IS-meIhyZ-IS-dehydro- 11 fi-hydroxyprogesterone 3,Z O-bis[ethylene ketal1) and 15 methyl 11a hydroxy 4,15 pregnadiene 3,20- dione 3,20-bis(elhylene ketal) (15-methyl-15-dehydr0- 11a hydroxyprogesterone 3,20 bis[ethylene ketal1) (XIHa) Following the procedure of Example 2, but employing 15-methyl-4,15-pregnadiene-3,11,20-trione 3 ,20-bis ethylene ketal) (XVII) as starting material, yields 15-methyl- :11 8 hydroxy 4,15 pregnadiene 3,20 bis(ethylene ketal) ()flIIa) and 15-metl1yl-11a-hydroxy-4,15-pregnadiene-3,20-dione 3,20-bis (ethylene ketal) (XIIIa).

EXAMPLE 16 15-methyl-11 3-hydr0xy-4J5-pregnadiene-3,20-dione (15- dehydro-15-methyl-1 LB-hydroxyprogesterone) (XIV) Following the procedure of Example 3, but substituting 15 methyl 11/3 hydroxy 4,15 pregnadiene 3,20- dione 3,20-bis(ethylene ketal) (XIIIa) as starting material, yields IS-methyl-l1,8-hydroxy-4,15-pregnadiene- 3,20-dione (XIV).

EXAMPLE 16A 15 methyl 11a lzydroxy 4,15 pregnadiene 3,20-dione 1 5 -dehydr-1 -m ethyl-1 1 whydroxyprogesterone) (XIV) Following the procedure of Example 3, but employing 15 methyl 11a hydroxy 4,15 pregnadiene 3,20- d-ione 3,20-bis(ethylene ketal) (XlHa) as starting material, yields IS-methyl-lla-hydroxy-4,15-pregnadiene-3,20- dione (XIV).

EXAMPLE 16B IS-meIhyZ-l] a-hydr0xy-4,15-pregnadiene-3,20 dione (XIV) Following the procedure of Example 3B, but substituting 15 methyl 11a hydroxy 4,15 pregnadiene- 3,20-dione ()GV) as starting material, is productive of 15- methyl-11a-hydroxy-4,15-pregnadiene-3,20-dione (XEV) EXAMPLE 17 ]5-methyl-4,15-pregnadiene-3,1J ,ZO-trione (15-methyl-J5- dehydrO-J 1 -ket0pr0gester0ne) (XV) and 3 ml. of pyridine was heated at 60 to 70 C. with stirring for a period of about 5 hours. The mixture was poured into water, extracted with methylene chloride and a the extracts washed successively with dilute acid, saturated sodium bicarbonate solution and water. The product was chromatographed over a column of 100 g. of Florisil and eluted with (1) acetone in Skellysolve B, (2) acetone in Skellysolve B and (3) acetone.

(a) The 15 eluates contained 0.118 g. of a crystalline product, identified as 4,14-pregnadiene-3,11,20-t1ione (X) by its infrared spectrum. Recrystallization of this material from a mixture of acetone and Skellysolve Byielded 0.5 g. of crystals with a melting point of 180 to 186 C. '(b) The aboveacetone fraction contained 1.02 g. of

oils and was rechromatographed over a column of g. of Florisil and eluted with mixtures of 15 and 20% acetone in Skellysolve B. The 15% acetone-Skellysolve B eluates contained 0.356 g. of an oil whose infrared spectrum exhibited characteristic tosyl ester absorption. Stripping the Florisil column with acetone yielded 0.149 g. of crude crystalline starting material, ISa-hydroxy-ll-ketoprogesterone (I), identified by its infrared spectrum.

(c) The 20% acetone-Skellysolve B eluates from (b), above, contained 0.43 g. of a crystalline compound whose infrared spectrum was very similar to that of ll-ketoprogesterone and gave a strong Beilstein test. Recrystallization of this fraction from acetone-Skellysolve B yielded 0.12 g. of crystalline 15e-chloro-4pregnene-3,11, 20-trione (H), with a melting point of 175 to 178 C. (decomposition) and a positive Beilstein test for halogen.

Analysis.-Calcd. for C H ClO C, 69.50; H, 7.50; CI, 9.77. Found: C, 69.72; H, 7.72; Cl, 9.01.

2:15" 1698, 1658, 1614. cmr

EXAMPLE 19 4-pregnene-3,11,20-trione 15a-p-t0luenesulf0nate (I 1 -ketoprogesterone 15a-p-t0luenesulf0nate) A mixture of 5 g. (0.0145 mole) of 15x-hydroxy-11- ketoprogesterone (I), 35 ml. of pyridine and 4 g. (0.021 mole) of p-toluenesulfonyl chloride was stirred at 25 C. for 7 days. After evaporation of the pyridine, the residual dark amber oil was chromatographed on a column of Florisil; elution with a mixture comprising 80% of petroleum ether and 20% of acetone gave 3.5 g. (48% yield) of the desired prod ct. Two recrystallizations from acetone-petroleum ether gave an analytical sample of 4- pregnene-3,1l,20-trione 15u-p-toluenesulfonate, having a melting point of 157 to 157.5 C.

Analysis.-Calcd. for C H O S: C, 67.44; H, S, 6.43. Found: C, 67.44; H, 6.83; S, 6.43.

xgfif 227 and 272 mp, =24,950 and 24,867

EXAMPLE 20 1 5 -br0m0-4-pregn ene-3 ,1 1,20-rrione (15-br0m0-1 1- ketoprogesterone) (II 1 g. of N-bromoacetamide was added to a solution of 2 g. of 15a-hydroxy-1l-ketoprogesterone (I) (Preparation 1) in 10 m1. of pyridine. The mixture was stirred for a period of about 10 minutes, cooled in an ice-bath, gaseous sulfur dioxide blown over its surface until no color change occurred, and then poured onto ice. The oil that separated was extracted with methylene chloride, washed with dilute hydrochloric acid and then with a saturated solution of sodium bicarbonate. The extract was filtered and the solvent evaporated under vacuum. The residue was recrystallized twice from a mixture of acetone and Skellysolve B to yield 1 g. of crystals of pure l5-bromo-4-pregnene-3,11,20-trione (II) melting at 133 to C. with decomposition. A second crop of 0.22 g. with an infrared spectrum identical to that of the main crop was obtained.

AnaIysis.-Calcd. for C l-1 0 131: C, 61.91; H, 6.68; Br, 19.62. Found: C, 62.27; H, 7.37; Br, 19.16. [d] +89 (acetone);

25 3 236.5 mg, e=

The infrared spectrum was similar to that of ll-ketoprogesterone and nearly identical with that reported above in Example 18(c) for 15B-chloro-4pregnene-3,l1,20-trione (H).

EXAMPLE 21 4,14-pregnadiene-3,1 1,20-tri0ne (14-dehydr0-1 1 -ketoprogesterone) (X) A crude preparation (melting point 126 to 134 C.) of

1.8 g. of 15-bromo-4-pregnene-3,11,20-trione (l1) (prepared as in Example 20) was heated at refluxing temperature with ml. of collidine for a period of about 5 minutes. After about one minute of heating a solid precipitated from the reaction mixture. The mixture was cooled, dissolved in methylene chloride, first washed with dilute hydrochloric acid and then with saturated sodium bicarbonate solution. The methylene chloride solution was evaporated under vacuum, leaving a crystalline residue. The infrared spectrum of this residue was found to be identical to that of 4,14-pregnadiene-3,11,20-trione (X).

Following the procedure of Example 21, but substituting l5-chloro-4-pregnene-3,11,20-trione (II) as starting material is also productive of 4,l4-pregnadiene-3,ll, 20-trione (X).

EXAMPLE 22 J5-methylene-4-pregnene-3,11,20-tri0ne 3,20-bis( ethylene ketal) (J5 methylene 11 ketoprogesterone 3,20-bis- [ethylene ketalJ) VII) A mixture of 24 g. of methyl triphenylphosphonium bromide and 260 ml. of benzene was distilled until the distillate was clear, after which the mixture was heated at refluxing temperature. 50 ml. of absolute ether was added thereto and then a suspension of 15 ml. of 26% n-butyl lithium in heptane added and the mixture heated at refluxing temperature for a period of about 90 minutes. A solution of 5 g. of 4-pregnene-3,l1,15,20-tetraone 3,20- bis(ethylene ketal) (VII) (synthesized as in Preparation 3) in 100 ml. of benzene was distilled sufficiently to remove the water contained therein, then added to the above-prepared reagent and heating of the mixture continued at refluxing temperature for a period of about 3 hours. The reaction mixture was cooled, diluted With water and the organic layer separated and washed successively with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, again with water and the solvent removed to yield a crystalline residue. This material was recrystallized from methanol to give 2.3 g. of product melting at 155 to 165 C. Purification of this product by chromatographing on a column of Florisil and elution therefrom with 3% acetone in Skellysolve B, yielded 15-methylene-4-pregnene-3,11,20-trione 3,20-bis- (ethylene ketal (VII') with a melting point of 175 to 179 C. following crystallization from acetone-hexanes. Further chromatography with acetone and Skellysolve B yielded the 3-rnonoethylene ketal of lS-methylene-4-pregnene-3,11,20-trione (2.6 g.) melting at 173- 180 C. A sample recrystallized from methanol melted at 173-178 C.

Analysis.Ca1cd. for C24H3204 C, H, Found: C, 74.32; H, 8.46. [0:1 (acetone) 1l0.

EXAMPLE 23 I5-methylene-4-pregnene-3,11,20-trione (IS-methylene- 1 -ket0 progesterone) VII'A Following the procedure of Example 1A, but substituting 1S-methylene-4-pregnene-3,11,20-trione 3,20-bis (ethylene ketal) (Vll) as starting compound, or the monoketal, above, there is thus produced l5-methylene-4-pregnene-3,ll,20-trione (VHA).

EXAMPLE 24 1 5 -methylene-1 1 8-hydroxy-4-pregnene 3,20 dione 3,20- bis( ethylene ketal) 1 5 -methylene-1 1 B-hydroxyprogesterone 3,20-bis[ethylene ketal] and -methylene-11 ahydr0xy-4-pregnene-3,20-di0ne 3,20-bis(ethylene ketal) (IS-methylene-J 1 ot-hydroxyprogesterone 3 ,ZO-bis [ethylene ketalJ) (VIIB) 7 Following the procedure of Example 2, but substituting 15-methylene-4-pregnene-3,l1,20-trione 3,20-bis(ethylene ketal) (VII) as starting compound, there is thus produced IS-methylene-l1B-hydroxy-4-pregnene-3,20-dione 3,20=bis(ethylene ketal) (VIIB) and l5=n1ethy1ene- EXAMPLE 26 15-methylene-11 a-hydr0xy-4-pregnene-3,20-dione (15- methylene-1 1 a-hydroxyprogesterone) (VII'C Following the procedure of Example 3A but substitut ing l5-methylene-l1a-hydroxy-4-pregnene-3,ZO-dione 3, 20-bis(ethylene ketal) (VIIB) as starting compound, there is thus produced 15-methylene-llu-hydroxy-4-pregnene-3,20-dione (VII'C).

EXAMPLE 27 IS-methylene-I1a-hydroxy-4-pregnene-3,20-di0ne (15- methylene-11 a-hydroxyprogesterone) VII'C) Following the procedure of Example 3B, but substitute ing 15 methylene 11B hydroxy 4 pregnene 3,20- dione (VllC) as starting compound, there is thus produced IS-methylene-lla-hydroxy-4-pregnene-3,20-dione (VII'Q).

We claim:

1. Compounds of the formula wherein X'is selected from the group consisting of the e-hydroxymethylene radical the m-hydroxymethylene radical and the carbonyl radical, C=O, Y is selected from the group consisting of hydrogen and methyl, and the 3,20- bis(alkylene ketals) thereof wherein the alkylene ketal radicals are of the formula wherein n is selected from the integers one and two and R is selected from the group consisting of hydrogen and a lower-alkyl radical containing from one to six carbon atoms, inclusive 2. 1lfl-hydroxy-4,l4-pregnadiene-3,20-dione. 3. 11u-hydroxy-4,l4-pregnadiene-3,ZO-dione.

4. 4,14-pregnadiene-3,l1,20-trione. 5. IS-methyl-l1,8-hydr0xy-4,14-pregnadiene-3,ZO-dione. 6. IS-methyl-l1a-hydroxy-4,l4-pregnadiene-3,20-dione. 7. 15-methyl-4,l4-pregnadiene -3J1,20-trione.

, 5 8. Compounds of the formula wherein X is selected from the group consisting of the fi-hydroxymethylene radical the a-hydroxymethylene radical [OH \C/ and the carbonyl radical, C=O, Y is selected from the group consisting of hydrogen and methyl, and the 3,20- bis(alkylene ketals) thereof wherein the alkylene ketal radicals are of the formula O-(CHah wherein X is selected from the group consisting of the B-hydroxymethylene radical OH \q/ the a-hydroxymethylene radical and the carbonyl radical, C=O, and the 3,20-bis(alkylene ketals) thereof wherein the alkylene ketal radicals are of the formula wherein n is selected from the integers one and two and R is selected from the group consisting of hydrogen and a lower-alkyl-radical containing from one to six carbon atoms, inclusive.

16. 15-methy1ene-l lfl-hydroxy-4-pregnene-3,20-dione.

17. 15-methylene-l1a-hydroxy-4-pregnene-3,20-dione.

l8. 15-methylene-4-pregnene-3,l1,20-trione.

19. A process for the production of a compound of the formula wherein n is an integer selected from the integers one and two, R is selected from the group consisting of hydrogen and a lower alkyl radical containing from one to six carbon atoms, inclusive, R is selected from the group consisting of hydrogen and a lower alkyl radical containing from one to six carbon atoms, inclusive, which comprises pyrolyzing a compound of the formula I? OH oo--o on.

l RHC-O wherein n, R and R have the same meanings as above.

20. A process for the production of l5-methyl-4,15 (l6)-pregnadiene-3,l1,20-t1i0ne 3,20-bis(ethylene ketal) of the formula /OCH1 K I x O-CH2 O CH CH,

HzC-O HzC-O which comprises pyrolyzing 15a-methyl-15fl-hydroxy4- pregnene-3,1l,20-trione 3,20-bis(ethylene ketal), IS-methylcarbonate ester of the formula ene-3,11,20- trione 3,20-bis(ethylene ketal) of the formula V e /OCH: c

Hz(]0 15' H243-O/ which comprises pyrolyzing 15p-hydr0xy-4-pregnene-3,

"2s 11,20-trione 3,20-bis(ethylene ketal), IS-methylcarbonate ester of the formula No references cited. 

1. COMPOUND OF THE FORMULA 